Antibodies Predict Pegaspargase Allergic Reactions and Failure of Rechallenge.

Abstract

PURPOSE:

Pegaspargase (PEG-ASP) has largely replaced native Escherichia coli asparaginase (L-ASP) in the treatment of acute lymphoblastic leukemia because of its longer half-life and lower immunogenicity. Risk factors for allergic reactions to PEG-ASP remain unclear. Here, we identify risk factors for reactions in a front-line acute lymphoblastic leukemia trial and assess the usefulness of serum antibodies for diagnosing allergy and predicting rechallenge outcome.

PATIENTS AND METHODS:

PEG-ASP was administered to 598 patients in St Jude's Total XVI study. Results were compared with Total XV study (ClinicalTrials.gov identifiers: NCT00549848 and NCT00137111), which used native L-ASP. Serum samples (n = 5,369) were analyzed for anti-PEG-ASP immunoglobulin G by enzyme-linked immunosorbent assay. Positive samples were tested for anti-polyethylene glycol (PEG) and anti-L-ASP. We analyzed potential risk factors for reactions and associations between antibodies and reactions, rechallenge outcomes, and PEG-ASP pharmacokinetics.

RESULTS:

Grade 2 to 4 reactions were less common in the Total XVI study with PEG-ASP (81 [13.5%] of 598) than in the Total XV study with L-ASP (169 [41.2%] of 410; P = 1.4 × 10-23). For Total XVI, anti-PEG, not anti-L-ASP, was the predominant component of anti-PEG-ASP antibodies (96%). In a multivariable analysis, more intrathecal therapy (IT) predicted fewer reactions (P = 2.4 × 10-5), which is consistent with an immunosuppressant contribution of IT. Anti-PEG-ASP was associated with accelerated drug clearance (P = 5.0 × 10-6). Failure of rechallenge after initial reactions was associated with anti-PEG-ASP (P = .0078) and was predicted by the occurrence of angioedema with first reaction (P = .01).

CONCLUSION:

Less IT therapy was the only independent clinical risk factor for reactions to PEG-ASP. PEG, and not L-ASP, is the major antigen that causes allergic reactions. Anti-PEG-ASP has utility in predicting and confirming clinical reactions to PEG-ASP as well as in identifying patients who are most likely to experience failure with rechallenge.

• Authors: Yiwei Liu, Colton A Smith, John C Panetta, Wenjian Yang, Lauren E Thompson, Jacob P Counts, Alejandro R Molinelli, Deqing Pei, Nancy M Kornegay, Kristine R Crews, Hope Swanson, Cheng Cheng, Seth E Karol, William E Evans, Hiroto Inaba, Ching-Hon Pui, Sima Jeha, Mary V Relling
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 37 Issue 23 Pg. 2051-2061 (08 10 2019) ISSN: 1527-7755 [Electronic] United States
• PMID: 31188727 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Antineoplastic Agents
• Polyethylene Glycols
• pegaspargase
• Asparaginase

Topics

• Antibodies (pharmacology, therapeutic use)
• Antineoplastic Agents (adverse effects)
• Asparaginase (adverse effects)
• Female
• Humans
• Hypersensitivity (etiology, pathology)
• Male
• Polyethylene Glycols (adverse effects)
• Risk Factors